Abstract Over the last ten years, the field of human genomics has made substantial progress in identifying genetic variants that influence disease risk. The emerging consensus is that many individuals at high risk for diseases like heart disease or breast cancer have high risk because of the combined action of many thousands of genetic variants across the genome in a polygenic manner. Identifying individuals at high polygenic risk of disease may lead to interventions of large public health importance. In this proposal, we will develop a low-pass sequencing assay that allows screening of an individual?s polygenic risk of disease in a cost-effective, scalable, and highly accurate manner, with an initial application to heart disease. As a proof of concept, we will perform both low-pass sequencing (to both 1x and 0.5x coverage) and genotyping (using the Illumina Global Screening Array) of 120 individuals and compare the estimated risk scores to those computed from gold standard genomes. In summary, we will develop a sequencing-based assay to calculate polygenic risk scores that is appropriate for population-scale application.